# NM_001371986.1(UNC80):c.3020G>C (p.Arg1007Pro)

https://sugi.bio/variant/unc80-p-arg1007pro

## Summary

**UNC80 p.Arg1007Pro (c.3020G>C)** is classified **Uncertain significance** in UNC80 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-03-15). AlphaMissense: ambiguous (0.4024); Very rare (popmax 0.00589%, amr); Associated with hypotonia, infantile, with psychomotor retardation and characteristic facies 2.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs202138404 · 3 submitters · 1 linked condition · AlphaMissense ambiguous · very rare (popmax 0.00589%, amr)

## For patients & families {#patients}

This is a change in the UNC80 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 3 submitters, and is linked to hypotonia, infantile, with psychomotor retardation and characteristic facies 2.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Diagnostic panels | UNC80 is a diagnostic-grade gene on 8 Genomics England panels |

**Commonly reported features of Hypotonia-speech impairment-severe cognitive delay syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Strabismus — Very frequent (99-80%)
- Esotropia — Very frequent (99-80%)
- Delayed speech and language development — Very frequent (99-80%)
- Global developmental delay — Very frequent (99-80%)
- Motor delay — Very frequent (99-80%)
- Absent speech — Very frequent (99-80%)
- Floppy infant — Very frequent (99-80%)
- Tapered distal phalanges of finger — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018458/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [UNC80](https://sugi.bio/atlas/gene/UNC80/) |
| Protein change (HGVS p.) | p.Arg1007Pro |
| Coding change (HGVS c.) | c.3020G>C |
| MANE Select transcript | [NM_001371986](https://www.ncbi.nlm.nih.gov/nuccore/NM_001371986) |
| dbSNP | [rs202138404](https://www.ncbi.nlm.nih.gov/snp/rs202138404/) |
| Variant type | single nucleotide variant |
| Location | chr2:209834989-209834989 (GRCh38) |
| ClinVar | [VCV1028451](https://www.ncbi.nlm.nih.gov/clinvar/variation/1028451/) |

**All HGVS expressions:** `NC_000002.11:g.210699713G>C`, `NC_000002.12:g.209834989G>C`, `NG_051361.1:g.68065G>C`, `NM_001371986.1:c.3020G>C`, `NM_032504.2:c.3020G>C`, `NM_182587.4:c.3005G>C`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense is indeterminate and SaProt makes no call here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.4024) — no call either way
- REVEL 0.226 (benign-leaning)
- SpliceAI predicts **donor loss** (Δ 0.20) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.802, GERP 1.87, phastCons 1 — highly conserved
- **SaProt:** not scored — SaProt is structure-aware and AlphaFold DB has no model for this protein. That is a property of the dataset, not of the variant, and is not evidence either way.
- CADD: **PHRED 25.8**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.84** across the covering region of the MANE Select transcript (209,834,087–209,917,930), spanning 83,843 bp. Chi-square p 1.2e-06. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.20**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.20**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.29** (loss), gain 0.01 / loss 0.29. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00589%** (amr) · FAF95 0.00439% · FAF99 0.00399% · 3/50,938 in the highest group · 68/1,550,380 alleles overall — very rare (popmax 0.00589%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00589% | 16,979 |
| European (non-Finnish) | 0.0055% | 18,194 |
| Remaining individuals (not grpmax-eligible) | 0.00166% | 60,112 |
| South Asian | 0.00119% | 84,020 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**UNC80** population constraint: LOEUF 0.48, pLI 0.0041479, missense-Z 5.0069; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **hypotonia, infantile, with psychomotor retardation and characteristic facies 2** — Definitive (AR)

## Protein context {#protein}

Residue **1007** lies in the 'disordered' region.

**3 experimental structure(s)** (PDB): [7SX3](https://www.rcsb.org/structure/7SX3), [7SX4](https://www.rcsb.org/structure/7SX4), [7WJI](https://www.rcsb.org/structure/7WJI).

## What this gene does {#gene-function}

*Describes the biological roles of UNC80 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*


### Pathways affected {#pathways}

UNC80 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Stimuli-sensing channels](https://reactome.org/content/detail/R-HSA-2672351) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Biological process:** sodium ion transmembrane transport, regulation of neuronal action potential.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2022-03-15.

**Submitter consensus:** unanimous (3/3 Uncertain significance).

**Submission history:** 3 submissions (2019–2022); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-11-22 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-03-15 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-10-18 |

## Associated conditions {#conditions}

[hypotonia, infantile, with psychomotor retardation and characteristic facies 2](https://sugi.bio/atlas/disease/hypotonia-infantile-with-psychomotor-retardation-and-characteristic-facies-2/).

**Reported phenotype names (ClinVar):** Hypotonia, infantile, with psychomotor retardation and characteristic facies 2, not provided, Inborn genetic diseases, UNC80 Deficiency, none provided.

## Similar variants {#similar}

Related UNC80 variant pages (same residue, condition, or type): [UNC80 p.Arg1007Cys](/variant/unc80-p-arg1007cys), [UNC80 p.Arg1007His](/variant/unc80-p-arg1007his), [UNC80 c.4110+1G>C](/variant/unc80-c-4110-plus-1g-c), [UNC80 c.8772+1G>A](/variant/unc80-c-8772-plus-1g-a), [UNC80 p.Arg1076Ter](/variant/unc80-p-arg1076ter), [UNC80 p.Arg1110Ter](/variant/unc80-p-arg1110ter), [UNC80 p.Arg1285Ter](/variant/unc80-p-arg1285ter), [UNC80 p.Arg1355Ter](/variant/unc80-p-arg1355ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1028451). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*